T cells are central players in initiating and maintaining immune responses. An important goal of successful immunotherapy is the stimulation of T cell immune responses against targets of interest such as tumors. This can be accomplished in two ways: 1) through immunization with tumor antigens or 2) by isolation of T cells specific to tumor antigens, and expansion of this population outside the body followed by re-transfer into the patient (adoptive transfer immunotherapy).
Preventative vaccines have eliminated smallpox and nearly eliminated polio, two of the worst global infectious diseases. By contrast vaccines for many other infectious diseases, such as malaria and HIV, which involve intracellular pathogens, are poorly developed or simply unavailable. The lack of such vaccines will result in two million unnecessary deaths each year in many parts of the world. Although economic factors play a role, there are a number of significant scientific challenges that have limited the development of vaccines for deadly diseases. First, few if any approaches are available that efficiently prime cell-mediated immunity by direct intracellular delivery of an antigen. Second, ‘tunable’ adjuvants, that is, adjuvants that can be engineered to optimize the magnitude and direction of an immune response, have not been developed. Third, the general requirement for parenteral (i.e. subcutaneous or intramuscular injection) administration of vaccines, a situation that has made it difficult to deploy vaccines in underdeveloped countries where medical support systems, resources, and even refrigeration are limited. Finally, there is a lack of a general approach to designing oral vaccines targeted to both systemic and mucosal immunity; oral vaccines are significantly less expensive to administer and transport. Thus, there is a critical need for safe and stable vaccine systems that would address these factors.
Some of the most encouraging data regarding immunotherapy come from studies employing adoptive transfer of tumor reactive T cells. Adoptive T cell transfer is an elegant approach to the treatment of infectious and malignant diseases. This therapeutic method involves the ex vivo expansion of T cells, which may be infused into patients to bolster the natural immune response. For example, expanded tumor-specific T cells have been shown to strengthen patient's immune responses to melanoma by infiltrating the tumor site and inducing tumor shrinkage. Researchers have also demonstrated that the adoptive transfer of T cells is a viable therapeutic approach to treating Epstein-Barr virus (EBV) as well as human immunodeficiency virus (HIV)-related infections. Thus, adoptive T cell transfer has potential applications in the treatment of both infectious diseases and cancer.
Despite the successes of these studies, adoptive T cell transfer by clonal expansion is not clinically viable since it does not consistently generate therapeutic numbers of T cells. This shortcoming has prompted the development of an alternative techniques for ex vivo T cell expansion, using artificial antigen presentation to T cells (Prakken, et al., Nat. Med., 6(12):1406-10 (2000); Oelke, et al., Nat. Med., 9(5):619-24 (2003); Kim, et al., Nat. Biotechn., 22:403-10 (2004)). The development of artificial APCs (aAPCs) is a new effort to generate a reproducible, “off-the shelf” means of stimulating and expanding T cells. Several types of aAPCs have been developed, including nonspecific bead-based systems that are currently used in many research laboratories to sustain the long-term expansion of CD8+ T cells (Oelke, et al., Nat. Med., 9(5):619-24 (2003); Kim, et al., Nat. Biotechn., 22:403-10 (2004)).
Specific expansion of T cells outside the body depends however on efficient methods for displaying protein ligands that stimulate those cells. Ultimately, T cell stimulus intensity depends on the density of bound receptors in the contact area with a surface (Andersen, et al., J. Biol. Chem., 276(52):49125-32 (2001); Gonzalez, et al., Proc. Natl. Acad. Sci. USA, 102(13):4824-9 (2005)). Regions with a high density of T cell antigen receptors have been termed activated clusters because they are critical for T cell stimulation (Grakoui, et al., Science, 285(5425:221-7 (1999); Monks, et al., Nature, 395(6697):82-6 (1998)). The presence of such high density clusters has also been shown to accelerate T cell activation (Gonzalez, et al., Proc. Natl. Acad. Sci. USA., 102(13):4824-9 (2005)). In the lymph node, the primary site for T cell stimulation, antigen presenting cells are thought to concentrate the presentation of T cell stimuli by trafficking in a dense architectural scaffolding in close proximity to T cells.
It is therefore an object of the invention to provide compositions that provide for high density presentation of ligands to T cell surface receptors.
It is another object of the invention to provide modular vaccine systems which provide for flexible addition of antigens and other elements.
It is another object of the invention to provide methods for activating T cells in vivo and ex vivo using compositions that provide high density ligand presentation.
It is yet another object of the invention to provide methods for activating and expanding T cells in vivo or ex vivo using compositions that provide high density presentation of T cell ligands.
It is still another object of the invention to provide methods for active and adoptive immunotherapy of diseases and disorders using compositions that provide high density presentation of T cell-activating ligands.